tbuckley/cabot-search huggingface dataset:
Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program
Authors: Meghana S Pagadala, Julie Lynch, Roshan Karunamuni, Patrick R Alba, Kyung Min Lee, Fatai Y Agiri, Tori Anglin, Hannah Carter, J Michael Gaziano, Guneet Kaur Jasuja, Rishi Deka, Brent S Rose, Matthew S Panizzon, Richard L Hauger, Tyler M Seibert
Journal: JNCI Journal of the National Cancer Institute (2022)

Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group.This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer.A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer.PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.
Ipsilateral Upper-Limb Lymphedema After COVID-19 Vaccine Booster
Authors: Charlene Yu Lin Tang, Wei Ming Chua
Journal: Clinical Nuclear Medicine (2022)

Abstract Recent data suggest that protective immunity from COVID-19 vaccine may wane after a period, with booster doses becoming increasingly deployed in many countries. An 84-year-old woman presents with a 6-month history of left upper-limb swelling; the only history of note was an intramuscular Pfizer-BioNTech mRNA vaccine booster in the ipsilateral deltoid just 1 week before the onset of the swelling. Upper-extremity lymphoscintigraphy after the administration of 99m Tc-nanocolloid into the interstitial space of the hands showed left upper-limb lymphatic dysfunction.
Metabolic reconfiguration enables synthetic reductive metabolism in yeast
Authors: Tao Yu, Quanli Liu, Xiang Wang, Xiangjian Liu, Yun Chen, Jens Nielsen
Journal: Nature Metabolism (2022)

Cell proliferation requires the integration of catabolic processes to provide energy, redox power and biosynthetic precursors. Here we show how the combination of rational design, metabolic rewiring and recombinant expression enables the establishment of a decarboxylation cycle in the yeast cytoplasm. This metabolic cycle can support growth by supplying energy and increased provision of NADPH or NADH in the cytosol, which can support the production of highly reduced chemicals such as glycerol, succinate and free fatty acids. With this approach, free fatty acid yield reached 40% of theoretical yield, which is the highest yield reported for Saccharomyces cerevisiae to our knowledge. This study reports the implementation of a synthetic decarboxylation cycle in the yeast cytosol, and its application in achieving high yields of valuable chemicals in cell factories. Our study also shows that, despite extensive regulation of catabolism in yeast, it is possible to rewire the energy metabolism, illustrating the power of biodesign.
Long-term pelvic fracture and overall mortality risk after pelvic cancer and pelvic radiation
Authors: Rebecca A Nelson, Andrew M Blakely, Joseph C Larson, Rowan T Chlebowski, Yi-Jen Chen, Jane A Cauley, Aladdin H Shadyab, Lily L Lai
Journal: JNCI Journal of the National Cancer Institute (2022)

The association of pelvic radiation with pelvic fracture risk has not been examined in prospective cohort settings with comprehensive fracture risk assessment, cancer-free comparison populations, and long-term follow-up. Our objective is to better characterize pelvic fracture and overall mortality risks in postmenopausal women participating in the Women's Health Initiative.A total of 135 743 Women's Health Initiative participants aged 50 to 79 years enrolled from 40 US clinical centers from 1993 to 1998 who had entry Fracture Risk Assessment Tool scores were eligible. Outcomes included pelvic cancer diagnosis, pelvic fracture occurrence, and mortality. Cox proportional hazards regression models were used to examine associations of pelvic cancer and pelvic radiation with pelvic fracture and mortality risk.After 17.7 years (median) follow-up, 4451 pelvic cancers, 10 139 pelvic fractures, and 33 040 deaths occurred. In multivariable analyses, women with incident pelvic cancer, compared with women who remained pelvic cancer free, had higher pelvic fracture risk (hazard ratio [HR] = 1.26, 95% confidence interval [CI] = 1.11 to 1.43) and higher overall mortality risk (HR = 2.91, 95% CI = 2.77 to 3.05). Women with pelvic cancer treated with pelvic radiation, compared with women with pelvic cancer not treated with pelvic radiation, had higher pelvic fracture risk (HR = 1.98, 95% CI = 1.41 to 2.78) and higher overall mortality after pelvic cancer (HR = 1.32, 95% CI = 1.15 to 1.52).Postmenopausal women with pelvic cancer, especially those receiving pelvic radiation, are at higher pelvic fracture risk and higher overall mortality risk. As therapeutic advances have reduced cancer mortality, attention to and interventions for pelvic fracture prevention may be important in pelvic cancer survivors.
BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma
Authors: Eshini Panditharatna, Joana G. Marques, Tingjian Wang, Maria C. Trissal, Ilon Liu, Li Jiang, Alexander Beck, Andrew Groves, Neekesh V. Dharia, Deyao Li, Samantha E. Hoffman, Guillaume Kugener, McKenzie L. Shaw, Hafsa M. Mire, Olivia A. Hack, Joshua M. Dempster, Caleb Lareau, Lingling Dai, Logan H. Sigua, Michael A. Quezada, Ann-Catherine J. Stanton, Meghan Wyatt, Zohra Kalani, Amy Goodale, Francisca Vazquez, Federica Piccioni, John G. Doench, David E. Root, Jamie N. Anastas, Kristen L. Jones, Amy Saur Conway, Sylwia Stopka, Michael S. Regan, Yu Liang, Hyuk-Soo Seo, Kijun Song, Puspalata Bashyal, William P. Jerome, Nathan D. Mathewson, Sirano Dhe-Paganon, Mario L. Suvà, Angel M. Carcaboso, Cinzia Lavarino, Jaume Mora, Quang-De Nguyen, Keith L. Ligon, Yang Shi, Sameer Agnihotri, Nathalie Y.R. Agar, Kimberly Stegmaier, Charles D. Stiles, Michelle Monje, Todd R. Golub, Jun Qi, Mariella G. Filbin
Journal: Cancer Discovery (2022)

Abstract Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.
The association between early life antibiotic exposure and the gut resistome of young children: a systematic review
Authors: Rebecca M. Lebeaux, Despina B. Karalis, Jihyun Lee, Hanna C. Whitehouse, Juliette C. Madan, Margaret R. Karagas, Anne G. Hoen
Journal: Gut Microbes (2022)

Antimicrobial resistance is a growing public health burden, but little is known about the effects of antibiotic exposure on the gut resistome. As childhood (0–5 years) represents a sensitive window of microbiome development and a time of relatively high antibiotic use, the aims of this systematic review were to evaluate the effects of antibiotic exposure on the gut resistome of young children and identify knowledge gaps. We searched PubMed, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials. A PICO framework was developed to determine eligibility criteria. Our main outcomes were the mean or median difference in overall resistance gene load and resistome alpha diversity by antibiotic exposure groups. Bias assessment was completed using RoB 2 and ROBINS-I with quality of evidence assessed via the GRADE criteria. From 4885 records identified, 14 studies (3 randomized controlled trials and 11 observational studies) were included in the qualitative review. Eight studies that included information on antibiotic exposure and overall resistance gene load reported no or positive associations. Inconsistent associations were identified for the nine studies that assessed resistome alpha diversity. We identified three main groups of studies based on study design, location, participants, antibiotic exposures, and indication for antibiotics. Overall, the quality of evidence for our main outcomes was rated low or very low, mainly due to potential bias from the selective of reporting results and confounding. We found evidence that antibiotic exposure is associated with changes to the overall gut resistance gene load of children and may influence the diversity of antimicrobial resistance genes. Given the overall quality of the studies, more research is needed to assess how antibiotics impact the resistome of other populations. Nonetheless, this evidence indicates that the gut resistome is worthwhile to consider for antibiotic prescribing practices.
Concerning data inconsistencies in Burkitt lymphoma genome study
Authors: Christopher K. Rushton, Kostiantyn Dreval, Ryan D. Morin
Journal: Blood (2022)

In 2019, a pair of studies described the whole-genome sequencing (WGS)-based characterization of over 100 Burkitt lymphomas (BLs). 1,2Panea et al 2 analyzed 101 patients representing sporadic, endemic, and HIV-associated clinical variants.Some of their conclusions were consistent with Grande et al 1 and others were contradictory and/or pointed to potential novel features of this disease.Panea et al nominated some new BL-related genes and highlighted the novelty of clustered noncoding mutations.To understand the factors leading to the divergent conclusions, we reanalyzed the sequencing data from Panea et al, which revealed several irregularities in their results that suggest serious errors in data processing.On reviewing the mutations reported in supplemental Table 2 of Panea et al (Panea_S2), we noted that 936 (40.1%) variants were attributed to at least 2 of 101 patients.It is exceedingly improbable for cancers from different individuals to share many identical mutations, with the exception of hotspot mutations, because of strong selective pressure.Although 264 variants were attributed to loci that are affected by aberrant somatic hypermutation, a process that increases the local mutation rate, most variants reported in multiple patients (672, 72%) were outside these regions and have no known biological explanation.
Oncogenic Addiction of Fibrolamellar Hepatocellular Carcinoma to the Fusion Kinase DNAJB1-PRKACA
Authors: Christoph Neumayer, Denise Ng, Caroline S. Jiang, Adam Qureshi, Gadi Lalazar, Roger Vaughan, Sanford M. Simon
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Gene fusions are drivers of many pediatric tumors. In fibrolamellar hepatocellular carcinoma (FLC), a fusion of DNAJB1 and PRKACA is the dominant recurrent mutation. Expression of the DNAJB1-PRKACA fusion gene in mice results in a tumor that recapitulates FLC. However, it is not known whether transient expression of DNAJB1-PRKACA is sufficient only to trigger tumor formation or whether ongoing expression is necessary for maintenance and progression. Experimental Design: We screened short hairpin RNAs (shRNA) tiled over the fusion junction and identified several potent and specific candidates in vitro and two independent FLC patient-derived xenografts (PDX). Results: We show that continued DNAJB1-PRKACA expression is not only required for continued tumor growth, but additionally its inhibition results in cell death. Inhibition of DNAJB1-PRKACA by an inducible shRNA in cells of PDX of FLC resulted in cell death in vitro. Induction of the shRNA inhibits FLC tumors growing in mice with no effect on xenografts from a hepatocellular carcinoma cell line engineered to express DNAJB1-PRKACA. Conclusions: Our results validate DNAJB1-PRKACA as the oncogene in FLC and demonstrate both a continued requirement for the oncogene for tumor growth as well as an oncogenic addiction that can be exploited for targeted therapies. We anticipate our approach will be useful for investigations of other fusion genes in pediatric cancers and spur development of precision therapies.
Brain Metastasis from HER2-Positive Breast Cancer: An Evolving Landscape
Authors: Riccardo Soffietti, Alessia Pellerino
Journal: Clinical Cancer Research (2022)

Summary Trastuzumab deruxtecan is a HER2-directed antibody–drug conjugate with ability to cross the blood–tumor barrier and activity on brain metastases. To test the activity of new drugs, patient-derived xenograft models from human brain metastases and phase 0 and window-of-opportunity trials are of utmost importance. See related article by Kabraji et al., p. 174
Association between heart failure quality of care and mortality: a population‐based cohort study using nationwide registries
Authors: Gorav Batra, Suleman Aktaa, Lina Benson, Ulf Dahlström, Camilla Hage, Gianluigi Savarese, Peter Vasko, Chris P. Gale, Lars H. Lund
Journal: European Journal of Heart Failure (2022)

Aims To evaluate the quality of heart failure (HF) care using the European Society of Cardiology (ESC) quality indicators (QIs) for HF and to assess whether better quality of care is associated with improved outcomes. Methods and results We performed a nationwide cohort study using the Swedish HF registry, consisting of patients with any type of HF at their first outpatient visit or hospitalization. Independent participant data for quality of HF care was evaluated against the ESC QIs for HF, and association with mortality estimated using multivariable Cox regression. In total, 43 704 patients from 80 hospitals across Sweden enrolled between 2013–2019 were included, with median follow‐up 23.6 months. Of the 16 QIs for HF, 13 could be measured and 5 were inversely associated with all‐cause mortality during follow‐up. Higher attainment (≥50% vs. &lt;50% attainment) of the composite opportunity‐based score (combination of QIs into a single score) for patients with reduced ejection fraction was associated with lower all‐cause mortality (adjusted hazard ratio 0.81; 95% confidence interval 0.72–0.91). Attainment of the composite score was less in the outpatient than inpatient setting (adjusted odds ratio 0.85; 95% confidence interval 0.72–0.99). Quality of care varied across hospitals, with assessment of health‐related quality of life being the indicator with the widest variation in attainment (interquartile range 61.7%). Conclusion Quality of HF care may be measured using the ESC HF QIs. In Sweden, attainment of HF care evaluated using the QIs demonstrated between and within hospital variation, and many QIs were inversely associated with mortality.
Senescence Rewires Microenvironment Sensing to Facilitate Antitumor Immunity
Authors: Hsuan-An Chen, Yu-Jui Ho, Riccardo Mezzadra, Jose M. Adrover, Ryan Smolkin, Changyu Zhu, Katharina Woess, Nicholas Bernstein, Georgia Schmitt, Linda Fong, Wei Luan, Alexandra Wuest, Sha Tian, Xiang Li, Caroline Broderick, Ronald C. Hendrickson, Mikala Egeblad, Zhenghao Chen, Direna Alonso-Curbelo, Scott W. Lowe
Journal: Cancer Discovery (2022)

Abstract Cellular senescence involves a stable cell-cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune-competent liver cancer model in which senescence triggers CD8 T cell–mediated tumor rejection, we show that senescence also remodels the cell-surface proteome to alter how tumor cells sense environmental factors, as exemplified by type II interferon (IFNγ). Compared with proliferating cells, senescent cells upregulate the IFNγ receptor, become hypersensitized to microenvironmental IFNγ, and more robustly induce the antigen-presenting machinery—effects also recapitulated in human tumor cells undergoing therapy-induced senescence. Disruption of IFNγ sensing in senescent cells blunts their immune-mediated clearance without disabling the senescence state or its characteristic secretory program. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals and imply that each process is required for their effective immune surveillance. Significance: Our work uncovers an interplay between tissue remodeling and tissue-sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance antitumor immunity. See the interview with Direna Alonso-Curbelo, PhD, recipient of the inaugural Cancer Discovery Early Career Award: https://vimeo.com/992987447 See related article by Marin et al., p. 410. This article is highlighted in the In This Issue feature, p. 247
Targeting cathepsin B by cycloastragenol enhances antitumor immunity of CD8 T cells via inhibiting MHC-I degradation
Authors: Guoliang Deng, Lisha Zhou, Binglin Wang, Xiaofan Sun, Qinchang Zhang, Hongqi Chen, Ning Wan, Hui Ye, Xiaoqi Wu, Dongdong Sun, Yang Sun, Haibo Cheng
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in Astragalus membranaceus , has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear. Methods The antitumor effect of CAG was investigated in MC38 and CT26 mouse transplanted tumor models. The antitumor effect of CAG was further analyzed via single-cell multiomics sequencing. Target responsive accessibility profiling technology was used to find the target protein of CAG. Subsequently, the antitumor mechanism of CAG was explored using confocal microscopy, coimmunoprecipitation and transfection of mutant plasmids. Finally, the combined antitumor effect of CAG and PD-1 antibodies in mice or organoids were investigated. Results We found that CAG effectively inhibited tumor growth in vivo. Our single-cell multiomics atlas demonstrated that CAG promoted the presentation of tumor cell-surface antigens and was characterized by the enhanced killing function of CD8 + T cells. Mechanistically, CAG bound to its target protein cathepsin B, which then inhibited the lysosomal degradation of major histocompatibility complex I (MHC-I) and promoted the aggregation of MHC-I to the cell membrane, boosting the presentation of the tumor antigen. Meanwhile, the combination of CAG with PD-1 antibody effectively enhanced the tumor killing ability of CD8 + T cells in xenograft mice and colorectal cancer organoids. Conclusion Our data reported for the first time that cathepsin B downregulation confers antitumor immunity and explicates the antitumor mechanism of natural product CAG.
BMJ journals collect gender, race, and ethnicity data on submissions
Authors: Mark Richards
Journal: BMJ (2022)

Capturing the diversity of our contributors systematically will enable better decision making Mark Richards article transfer service managerEquity, diversity, and inclusion (EDI) are at the heart of BMJ's mission to create a healthier and more equitable world.Research has shown that greater gender, racial, and ethnic diversity; representation of disadvantaged voices; and inclusion of different perspectives enable better decision making.
The universal stem cell
Authors: Peter J. Quesenberry, Sicheng Wen, Laura R. Goldberg, Mark S. Dooner
Journal: Leukemia (2022)

Abstract Current dogma is that there exists a hematopoietic pluripotent stem cell, resident in the marrow, which is quiescent, but with tremendous proliferative and differentiative potential. Furthermore, the hematopoietic system is essentially hierarchical with progressive differentiation from the pluripotent stem cells to different classes of hematopoietic cells. However, results summarized here indicate that the marrow pluripotent hematopoietic stem cell is actively cycling and thus continually changing phenotype. As it progresses through cell cycle differentiation potential changes as illustrated by sequential changes in surface expression of B220 and GR-1 epitopes. Further data indicated that the potential of purified hematopoietic stem cells extends to multiple other non-hematopoietic cells. It appears that marrow stem cells will give rise to epithelial pulmonary cells at certain points in cell cycle. Thus, it appears that the marrow “hematopoietic” stem cell is also a stem cell for other non-hematopoietic tissues. These observations give rise to the concept of a universal stem cell. The marrow stem cell is not limited to hematopoiesis and its differentiation potential continually changes as it transits cell cycle. Thus, there is a universal stem cell in the marrow which alters its differentiation potential as it progresses through cell cycle. This potential is expressed when it resides in tissues compatible with its differentiation potential, at a particular point in cell cycle transit, or when it interacts with vesicles from that tissue.
Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol, Florence, Italy, August 2021 to June 2022
Authors: Marco Coppi, Alberto Antonelli, Claudia Niccolai, Andrea Bartolini, Laura Bartolini, Maddalena Grazzini, Elisabetta Mantengoli, Alberto Farese, Filippo Pieralli, Maria Teresa Mechi, Vincenzo Di Pilato, Tommaso Giani, Gian Maria Rossolini
Journal: Eurosurveillance (2022)

A nosocomial outbreak by cefiderocol (FDC)-resistant NDM-1-producing Klebsiella pneumoniae (NDM-Kp) occurred in a large tertiary care hospital from August 2021–June 2022 in Florence, Italy, an area where NDM-Kp strains have become endemic. Retrospective analysis of NDM-Kp from cases observed in January 2021–June 2022 revealed that 21/52 were FDC-resistant. The outbreak was mostly sustained by clonal expansion of a mutant with inactivated cirA siderophore receptor gene, which exhibited high-level resistance to FDC (MIC ≥ 32 mg/L) and spread independently of FDC exposure.